Cystic fibrosis transmembrane conductance regulator inverts protein kinase A-mediated regulation of epithelial sodium channel single channel kinetics
Cystic fibrosis transmembrane conductance regulator inverts protein kinase A-mediated regulation of epithelial sodium channel single channel kinetics
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DOI：
10.1074/jbc.272.22.14037
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发表时间：
1997-05-30
影响因子：
4.8
通讯作者：
Boucher, RC
中科院分区：
文献类型：
--
作者：
Stutts, MJ;Rossier, BC;Boucher, RC
ABC转运蛋白超家族成员对离子通道的异常调节与囊性纤维化的高胰岛素血症和呼吸道上皮细胞对Na+的过度吸收有关。ABC蛋白如何调节离子电导尚不清楚，但通常必须涉及特定离子通道的数量或活性。在此，我们报道囊性纤维化跨膜电导调节器(CFTR)，它在CF中是有缺陷的，它逆转了cAMP对单一上皮钠通道(ENaC)活性的调节。在成纤维细胞中单独表达的ENAC对cAMP依赖的蛋白激酶的激活具有更高的开放概率(P-o)和平均开放时间，而与CFTR共表达的ENaC在PKA介导的蛋白磷酸化的最佳条件下表现出降低的P-o和平均开放时间。因此，CFTR通过将单通道P-o对cAMP的反应从增加切换到减少，在单通道门控水平上调节ENaC。
Abnormal regulation of ion channels by members of the ABC transport protein superfamily has been implicated in hyperinsulinemic hypoglycemia and in excessive Na+ absorption by airway epithelia in cystic fibrosis (CF). How ABC proteins regulate ion conductances is unknown, but must generally involve either the number or activity of specific ion channels. Here we report that the cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in CF, reverses the regulation of the activity of single epithelial sodium channels (ENaC) by cAMP. ENaC expressed alone in fibroblasts responded to activation of cAMP-dependent protein kinase with increased open probability (P-o) and mean open time, whereas ENaC co-expressed with CFTR exhibited decreased P-o and mean open time under conditions optimal for PKA-mediated protein phosphorylation. Thus, CFTR regulates ENaC at the level of single channel gating, by switching the response of single channel P-o to cAMP from an increase to a decrease.